The frequency of Staphylococcus aureus infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate Staphylococcus aureus strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
The Clp ATPases constitute a recently discovered family that is represented in every organism examined thus far. They appear to serve at least two roles in the cell. They are involved in the regulation of proteolysis by activating the ClpP protease in the ATP-dependent cleavage of denatured proteins. (Squires & Squires, 1992, The Clp Proteins: Proteolysis regulators or molecular chaperones? Journal of Bacteriology 174:1081-5). They are also molecular chaperones which can function independently of ClpP protease, and are capable of repairing proteins damaged during stress conditions (Wawrzynow A., Banecki, B. & Zylicz, M., 1996,. The Clp ATPases define a novel class of molecular chaperones. Molecular Microbiology 21:895-9). Microorganisms such as Staphylococcus aureus are under a variety of environmental stresses in vivo, and it can be expected that members of the Clp ATPase family will play a role in survival and growth of the pathogen during infection. Consistent with this is the discovery of a gene encoding a Clp-like protein which is expressed in vivo. Inhibition of the function of this protein is likely to impair the ability of Staphylococcus aureus to establish and maintain an infection.
Clearly, there is a need for factors, such as the compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known Lactococcus lactis clpL protein.